Inhibitors of IRAK4 activity

ABSTRACT

The present invention relates to inhibitors of IRAK4 of Formula I and provides compositions comprising such inhibitors, as well as methods therewith for treating IRAK4-mediated or -associated conditions or diseases.

BACKGROUND OF THE INVENTION

The present invention is directed to compounds which modulateinterleukin-1 (IL-1) receptor-associated kinase 4 (IRAK4) and are usefulin the prevention or treatment of inflammatory, cell proliferative andimmune-related conditions and diseases.

The recruitment of immune cells to sites of injury involves theconcerted interactions of a large number of soluble mediators. Severalcyctokines appear to play key roles in these processes, particularlyIL-1 and TNF. Both cytokines are derived from mononuclear cells andmacrophages, along with other cell types. Physiologically, they producemany of the same proinflammatory responses, including fever, sleep andanorexia, mobilization and activation of polymorphonuclear leukocytes,induction of cyclooxygenase and lipoxygenase enzymes, increase inadhesion molecule expression, activation of B-cells, T-cells and naturalkiller cells, and stimulation of production of other cytokines. Otheractions include a contribution to the tissue degeneration observed inchronic inflammatory conditions, such as stimulation of fibroblastproliferation, induction of collagenase, etc. They have also beenimplicated in the process of bone resorption and adipose tissueregulation. Thus, these cytokines play key roles in a large number ofpathological conditions, including rheumatoid arthritis, inflammatorybowel disease, multiple sclerosis, diabetes, obesity, cancer, sepsis,etc.

The importance of IL-1 in inflammation has been demonstrated by theability of the highly specific IL-1 receptor antagonist protein (IL-1Raor IRAP) to relieve inflammatory conditions. See, e.g., Dinarello,Cytokine Growth Factor Rev., 1997, 8:253-265.

IL-1 treatment of cells induces the formation of a complex consisting ofthe two IL-1 receptor chains, IL-1R1 and IL-1RAcP, and the resultingheterodimer recruits an adaptor molecule designated as MyD88. See e.g.,Wesche et al., J. Biol. Chem., 1999, 274:19403-19410. MyD88 binds to aprotein designated IRAK (IL-1 receptor associated kinase). See, e.g.,O'Neill et al., J. Leukoc. Biol., 1998, 63(6):650-657; Auron, CytokineGrowth Factor Rev., 1998, 9(3-4):221-237; and O'Neill, Biochem. Soc.Trans., 2000, 28(5):557-563. IRAK is subsequently phosphorylated andreleased from the receptor complex to interact with a tumor necrosisfactor receptor-associated factor, TRAF6, which transduces the signal todownstream effector molecules. See e.g., Cao et al., Nature, 1996,383:443-446. TRAF6 can trigger the NIK/IKK kinase cascade to activatethe transcription factor NK-kappa B. NF-kappa B regulates a number ofgenes that, in turn, regulate immune and inflammatory responses.

Four IRAKs have been identified: IRAK1 (see, e.g., Cao et al., Science,1996, 271:1128-1131), IRAK2 (see, e.g. Muzio et al., Science, 1997,278:1612-1615), the monomyeloic cell specific IRAKM, also known as IRAK3(see, e.g., Wesche et al., J. Biol. Chem., 1999, 274:19403-19410), andIRAK4 (see, e.g., PCT Publication No. WO 01/051641). IRAK proteins havebeen shown to play a role in transducing signals other than thoseoriginating from IL-1 receptors, including signals triggered byactivation of IL-18 receptors (see, e.g., Kanakaraj et al., J. Exp.Med., 1999, 189(7):1129-1138) and LPS receptors (see, e.g., Yang et al.,J. Immunol., 1999, 163:639-643; and Wesche et al., J. Biol. Chem., 1999,274:19403-19410). Over-expression of IRAK2 and IRAKM has been shown tobe capable of reconstituting the response to IL-1 and LPS in an IRAKdeficient cell line.

The identification of compounds that inhibit the function of IRAK4represents an attractive approach to the development of therapeuticagents for the treatment of inflammatory, cell proliferative andimmune-related conditions and diseases associated with IRAK4-mediatedsignal transduction, such as rheumatoid arthritis, inflammatory boweldisease, multiple sclerosis, diabetes, obesity, allergic disease,psoriasis, asthma, graft rejection, cancer, and sepsis.

It is an object of the instant invention to provide novel compounds thatare inhibitors of IRAK4.

It is also an object of the present invention to provide pharmaceuticalcompositions that comprise the novel compounds that are inhibitors ofIRAK4.

It is also an object of the present invention to provide a method fortreating IRAK4-mediated and associated conditions or diseases thatcomprises administering such inhibitors of IRAK4 activity.

SUMMARY OF THE INVENTION

The present invention relates to inhibitors of IRAK4 of formula (I) andprovides compositions comprising such inhibitors, as well as methodstherewith for treating IRAK4-mediated or -associated conditions ordiseases.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the instant invention are useful in the inhibition ofthe activity of IRAK4.

An embodiment of the instant invention is illustrated by the Formula I:

wherein:

X is NH or O;

b is 0 or 1;

n is 0, 1, 2, 3 or 4;

R₁ and R₂ are independently H and (C₁-C₄)alkyl, or R₁ and R₂ can betaken together with the nitrogen to which they are attached to form amonocyclic or bicyclic (fused, bridged or spirocyclic) heterocyclecontaining 3-8 carbon atoms optionally containing, in addition to thenitrogen, one or two additional heteroatoms selected from N, O and S,said alkyl and heterocycle are optionally substituted with one or moresubstituents selected from R_(a);

R₃ is (C₁-C₄)alkyl wherein two adjacent alkyl groups can join togetherand form a bridged moiety of 3-6 carbon atoms;

R₄ is absent, halo or O_(b)(C₁-C₄)alkyl;

R₅ is halo, CN and O(C₁-C₄)alkyl, said alkyl optionally substituted withone or more substituents selected from CN and (C═O)NH₂;

R₆ is absent, halo, or O(C₁-C₄)alkyl;

R_(a) is independently selected from halo, CF₃, O_(b)(C₁-C₄)alkyl,SO₂(C₁-C₄)alkyl, C(O) O_(b)(C₁-C₆)alkyl, (C═O)_(b)heterocyclyl, whereinsaid alkyl can come together with another alkyl to form a bridged moietyand wherein said alkyl and heterocyclyl are optionally substituted withR_(b); and

R_(b) is independently selected from OH, halo, SO₂(C₁-C₄)alkyl,O_(b)(C₁-C₄)alkyl, and heterocyclyl;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

Another embodiment of the instant invention is illustrated by theFormula I:

wherein:

X is NH or O;

b is 0 or 1;

n is 0, 1, 2, 3 or 4;

R₁ and R₂ are independently H and (C₁-C₄)alkyl, or R₁ and R₂ can betaken together with the nitrogen to which they are attached to form amonocyclic or bicyclic (fused, bridged or spirocyclic) heterocyclecontaining 3-8 carbon atoms optionally containing, in addition to thenitrogen, one or two additional heteroatoms selected from N, O and S,said alkyl and heterocycle are optionally substituted with one or moresubstituents selected from R_(a);

R₃ is methyl wherein two adjacent methyl groups can join together andform a bridged moiety of 3-6 carbon atoms;

R₄ is absent or (C₁-C₄)alkyl;

R₅ is halo, CN and O(C₁-C₄)alkyl, said alkyl optionally substituted withone or more substituents selected from CN and (C═O)NH₂;

R₆ is absent, halo, or O(C₁-C₄)alkyl;

R_(a) is independently selected from halo, CF₃, O_(b)(C₁-C₄)alkyl,SO₂(C₁-C₄)alkyl, C(O) O_(b)(C₁-C₆)alkyl, heterocyclyl,C═O-tetrahydrofuranyl, wherein said alkyl can come together with anotheralkyl for form a bridged moiety and wherein said alkyl and heterocyclylare optionally substituted with R_(b); and

R_(b) is independently selected from OH, halo, SO₂(C₁-C₄)alkyl,O_(b)(C₁-C₄)alkyl, morpholinyl and oxetanyl;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

Another embodiment of the instant invention is illustrated by theFormula I:

wherein:

X is NH or O;

b is 0 or 1;

n is 0, 1 or 2;

R₁ and R₂ are independently H and (C₁-C₄)alkyl, or R₁ and R₂ can betaken together with the nitrogen to which they are attached to formmorpholinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolinyl,pyrhexahydrocyclopentaoxazinyl, hexahydropyranopyridinyl,hexahydrofuropyrrolyl, azabicyclooctyl, oxaazabicyclooctyl and azapanyl,said alkyl, morpholinyl, piperidinyl, azetidinyl, piperazinyl,pyrrolinyl, pyrhexahydrocyclopentaoxazinyl, hexahydropyranopyridinyl,hexahydrofuropyrrolyl, azabicyclooctyl, oxaazabicyclooctyl and azapanylare optionally substituted with one or more substituents selected fromR_(a);

R₃ is methyl wherein two adjacent methyl groups can come together andform a bridged moiety;

R₄ is absent or methyl;

R₅ is selected from: Br, F, Cl, CN and O(C₁-C₄)alkyl, said alkyloptionally substituted with one or more substituents selected from CNand (C═O)NH₂;

R₆ is absent, halo, or CH₃;

R_(a) is independently selected from F, CF₃, O_(b)(C₁-C₄)alkyl,SO₂(C₁-C₄)alkyl, C(O) O_(b)(C₁-C₆)alkyl, heterocyclyl,C═O-tetrahydrofuran, wherein said alkyl can come together with anotheralkyl for form a bridged moiety and wherein said alkyl and heterocyclylare optionally substituted with R_(b); and

R_(b) is independently selected from OH, halo, SO₂(C₁-C₄)alkyl,O_(b)(C₁-C₄)alkyl, morpholinyl and oxetanyl;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

A compound of the instant invention is selected from:

-   4-[(trans-4-aminocyclohexyl)amino]quinazoline-6-carbonitrile;-   trans-N-(6-bromoquinazolin-4-yl)cyclohexane-1,4-diamine;-   6-bromo-4-{[trans-4-(morpholin-4-yl)cyclohexyl]oxy}quinazoline;-   6-bromo-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine;-   trans-N′-(6,7-dimethoxyquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine;-   trans-N′-(6,7-difluoroquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine;-   4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazoline-6-carbonitrile;-   trans-N′-(6-bromoquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine;-   4-{[trans-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   6-methoxy-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine;-   6-fluoro-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine;-   N-[trans-4-(morpholin-4-yl)cyclohexyl]-6-(propan-2-yloxy)quinazolin-4-amine;-   6-bromo-7-fluoro-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine;-   7-fluoro-6-methoxy-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine;-   6-chloro-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine;-   trans-N′-(6-methoxyquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine;-   [(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)oxy]acetonitrile;-   4-[(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)oxy]butanenitrile;-   2-[(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)oxy]acetamide;-   4-{[(1S,6R)-5-(morpholin-4-yl)bicyclo[4.1.0]hept-2-yl]amino}quinazoline-6-carbonitrile;-   4-{[trans-4-(azetidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({cis or trans-4-[(3R or    S)-3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({cis or trans-4-[(3R or    S)-3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({cis or trans-4-[(3R or    S)-3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({cis or trans-4-[(3R or    S)-3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[cis-4-(azetidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-{[trans-4-(2,3-dimethylmorpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-{[cis-4-(2,3-dimethylmorpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({trans-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4[4-(methylsulfonyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(2R or    2S)-2-(hydroxymethyl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(2R or    2S)-2-(hydroxymethyl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[3-(methylsulfonyl)pyrrolidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(2S,6S or    2R,6R)-2,6-dimethylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(2S,6S or    2R,6R)-2,6-dimethylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(2S or    2R)-2-methylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(2S or    2R)-2-methylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[trans-4-(4-fluoropiperidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({trans-4-[4-(methylsulfonyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(2-methoxyethyl)amino]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[trans-4-(cyclopropylamino)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({trans-4-[(4aS,7aS or    4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[trans-4-(hexahydro-2H-pyrano[4,3-b]pyridin-1(5H)-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-{[trans-4-(4-oxa-7-azaspiro[2.5]oct-7-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({trans-4-[2-(fluoromethyl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(3S)-3-methylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-{[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({trans-4-[(3R)-3-methylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[cyclopropyl(methyl)amino]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[trans-4-(3,3-difluoropiperidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({trans-4-[(3S)-3-hydroxypyrrolidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[trans-4-(3-fluoropiperidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-{[trans-4-(3-hydroxy-3-methylpyrrolidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({trans-4-[3-(morpholin-4-yl)azetidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(3R)-3-hydroxypyrrolidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[trans-4-(hexahydro-4H-furo[3,2-b]pyrrol-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({trans-4-[(3R)-3-methoxypyrrolidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(3R or    3S)-3-(morpholin-4-ylmethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(3R or    3S)-3-(morpholin-4-ylmethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[4-(morpholin-4-ylmethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[trans-4-(pyrrolidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   tert-butyl    4-{trans-4-[(6-cyanoquinazolin-4-yl)amino]cyclohexyl}piperazine-1-carboxylate;-   4-({trans-4-[3-(morpholin-4-ylmethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[trans-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({trans-4-[(2R or    2S)-2-(trifluoromethyl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(2R or    2S)-2-(trifluoromethyl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[(1R,5S)-8-oxa-3-azabicyclo[3.2.1]oct-3-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[trans-4-(2,2-dimethylmorpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({trans-4-[(3R)-3-(propan-2-yl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[trans-4-(4,4-difluoroazepan-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-{[trans-4-(4,4-difluoropiperidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-{[trans-4-(3-hydroxypyrrolidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-[(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)oxy]butanamide;-   7-fluoro-4-{[trans-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   5-methyl-4-{[trans-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({trans-4-[4-(cyclopropylcarbonyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-{[trans-4-(4-acetylpiperazin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-({trans-4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[4-(3-fluoro-2,2-dimethylpropanoyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[4-(2-fluoro-2-methylpropanoyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[4-(2,2-difluoropropanoyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[4-(2-fluoropropanoyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-[(trans-4-{4-[(1-methylcyclopropyl)carbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile;-   4-[(trans-4-{4-[(3-methyloxetan-3-yl)carbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile;-   4-({trans-4-[4-(methoxyacetyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-[(trans-4-{4-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile;-   4-({trans-4-[4-(difluoroacetyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-[(trans-4-{4-[(3-fluorocyclobutyl)carbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile;-   4-[(trans-4-{4-[(2,2-difluorocyclopropyl)carbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile;-   4-({trans-4-[4-(cyclobutylcarbonyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[4-(cyclopentylcarbonyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[4-(cyclopropylacetyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[4-(oxetan-3-ylacetyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-({trans-4-[4-(fluoroacetyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-[(trans-4-{4-[cyclopropyl(hydroxy)acetyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile;-   4-[(trans-4-{4-[(3-hydroxycyclobutyl)carbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile;-   4-({trans-4-[4-(3-hydroxypropanoyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;-   4-[(trans-4-{4-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile;-   4-{[trans-1-methyl-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-{[trans-4-(4-fluoropiperidin-1-yl)-1-methylcyclohexyl]amino}quinazoline-6-carbonitrile;-   4-{[trans-4-(3-hydroxypyrrolidin-1-yl)-1-methylcyclohexyl]amino}quinazoline-6-carbonitrile;-   4-{[(1S,2S,5S,6R)-5-(4-fluoropiperidin-1-yl)bicyclo[4.1.0]hept-2-yl]amino}quinazoline-6-carbonitrile;-   4-{[(1R,2R,4R or    1S,2S,4S)-2-methyl-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   4-{[(1S,2S,4S or    1R,2R,4R)-4-(4-fluoropiperidin-1-yl)-2-methylcyclohexyl]amino}quinazoline-6-carbonitrile;    and-   4-{[(1S,2R,4S or    1R,2S,4R)-2-methyl-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;-   or a pharmaceutically acceptable salt or stereoisomer thereof.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, all such stereoisomers beingincluded in the present invention.

In addition, the compounds disclosed herein may exist as tautomers andboth tautomeric forms are intended to be encompassed by the scope of theinvention, even though only one tautomeric structure is depicted.

This invention is also intended to encompass pro-drugs of the compoundsdisclosed herein. A prodrug of any of the compounds can be made usingwell known pharmacological techniques.

When any variable (e.g. R₃, etc.) occurs more than one time in anyconstituent, its definition on each occurrence is independent at everyother occurrence. Also, combinations of substituents and variables arepermissible only if such combinations result in stable compounds. Linesdrawn into the ring systems from substituents represent that theindicated bond may be attached to any of the substitutable ring atoms.If the ring system is bicyclic, it is intended that the bond be attachedto any of the suitable atoms on either ring of the bicyclic moiety. WhenR₄ and/or R₆ are “absent” it is understood that a hydrogen atom ispresent.

In the compounds of Formula I, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of Formula I. Forexample, different isotopic forms of hydrogen (H) include protium (1H)and deuterium (2H). Protium is the predominant hydrogen isotope found innature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundswithin Formula I can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Scheme and Examples hereinusing appropriate isotopically-enriched reagents and/or intermediates.

It is understood that one or more silicon (Si) atoms can be incorporatedinto the compounds of the instant invention in place of one or morecarbon atoms by one of ordinary skill in the art to provide compoundsthat are chemically stable and that can be readily synthesized bytechniques known in the art from readily available starting materials.Carbon and silicon differ in their covalent radius leading todifferences in bond distance and the steric arrangement when comparinganalogous C-element and Si-element bonds. These differences lead tosubtle changes in the size and shape of silicon-containing compoundswhen compared to carbon. One of ordinary skill in the art wouldunderstand that size and shape differences can lead to subtle ordramatic changes in potency, solubility, lack of off target activity,packaging properties, and so on. (Diass, J. O. et al. Organometallics(2006) 5:1188-1198; Showell, G. A. et al. Bioorganic & MedicinalChemistry Letters (2006) 16:2555-2558).

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.In some instances, two substituents are attached to the same carbon andcome together to form a carbocyclic or heterocyclic ring (a spirocyclicring system).

As used herein, “alkyl” is intended to include branched, cyclic andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₄, as in“(C₁-C₄)alkyl” is defined to include groups having 1, 2, 3, and 4 carbonatoms in a linear, cyclic or branched arrangement. For example,“(C₁-C₄)alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, i-butyl, cyclopropyl, and cyclobutyl. For example,C₁-C₆, as in “(C₁-C₆)alkyl” is defined to include groups having 1, 2, 3,4, 5 and 6 carbon atoms in a linear, cyclic or branched arrangement. Forexample, “(C₁-C₆)alkyl” specifically includes methyl, ethyl, n-propyl,i-propyl, n-butyl, t-butyl, i-butyl, cyclopropyl cyclobutyl, cyclopenyland cyclohexyl.

The term “heterocycle” as used herein is intended to mean a 3- to10-membered aromatic or nonaromatic heterocycle containing from 1 to 4heteroatoms selected from the group consisting of O, N and S, andincludes monocyclic or bicyclic groups (fused, bridged or spirocyclic).“Heterocycle” therefore includes heteroaryls, as well as dihydro andtetrathydro analogs thereof. Further examples of “heterocycle” include,but are not limited to the following: benzoimidazolyl,benzoimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl,indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline,isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl,tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof.

In one embodiment of Formula I, heterocycle is selected frombenzoimidazolyl, benzoimidazolonyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof, optionally substituted with one to three substituentsindependently selected from R_(a).

In another embodiment of Formula I, heterocycle is selected frombenzoimidazolyl, benzoimidazolonyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl and thiomorpholinyl.

In another embodiment of Formula I, heterocycle is selected from:oxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl,thienyl, triazolyl, azetidinyl, piperazinyl, piperidinyl, pyrrolidinyl,and morpholinyl.

In another embodiment of Formula I, heterocycle is selected from:azetidinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, andmorpholinyl.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro (Cl), fluoro (F), bromo (Br) andiodo (I).

In another embodiment, X is NH.

In another embodiment, X is O.

In another embodiment, R₃ is methyl, wherein two adjacent methyl groupscan join together and form a bridged moiety.

In another embodiment, n is 0, 1, or 2.

In another embodiment, n is 0 or 1.

In another embodiment, n is 1.

In another embodiment, n is 0.

Included in the instant invention is the free form of compounds ofFormula I as well as the pharmaceutically acceptable salts andstereoisomers thereof. Some of the isolated specific compoundsexemplified herein are the protonated salts of amine compounds. The term“free form” refers to the amine compounds in non-salt form. Theencompassed pharmaceutically acceptable salts not only include theisolated salts exemplified for the specific compounds described herein,but also all the typical pharmaceutically acceptable salts of the freeform of compounds of Formula I. The free form of the specific saltcompounds described may be isolated using techniques known in the art.For example, the free form may be regenerated by treating the salt witha suitable dilute aqueous base solution such as dilute aqueous NaOH,potassium carbonate, ammonia and sodium bicarbonate. The free forms maydiffer from their respective salt forms somewhat in certain physicalproperties, such as solubility in polar solvents, but the acid and basesalts are otherwise pharmaceutically equivalent to their respective freeforms for purposes of the invention.

The pharmaceutically acceptable salts of the instant compounds can besynthesized from the compounds of this invention which contain a basicor acidic moiety by conventional chemical methods. Generally, the saltsof the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed by reacting a basic instant compound with aninorganic or organic acid. For example, conventional non-toxic saltsinclude those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, aswell as salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic(TFA) and the like.

When the compound of the present invention is acidic, suitable“pharmaceutically acceptable salts” refers to salts prepared formpharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N1-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19.

It will also be noted that the compounds of the present invention arepotentially internal salts or zwitterions, since under physiologicalconditions a deprotonated acidic moiety in the compound, such as acarboxyl group, may be anionic, and this electronic charge might then bebalanced off internally against the cationic charge of a protonated oralkylated basic moiety, such as a quaternary nitrogen atom.

Utility

According to another embodiment, the present invention provides a methodof treating or reducing the severity of a disease in a patient by usinga compound of Formulas I as described above, wherein said disease isselected from IRAK4 mediated pathologies, such as rheumatoid arthritis,multiple sclerosis, sepsis, osteoarthritis, inflammatory bowel disease,Parkinson's disease, cardiac contractile dysfunction, type I diabetes,type II diabetes or familial cold autoinflammatory syndrome, allergicdisease, cancer, lupus, psoriasis, asthma or graft rejection.

The compounds of the invention find use in a variety of applications. Aswill be appreciated by those skilled in the art, the kinase activity ofIRAK4 may be modulated in a variety of ways; that is, one can affect thephosphorylation/activation of IRAK4 either by modulating the initialphosphorylation of the protein or by modulating the autophosphorylationof the other active sites of the protein. Alternatively, the kinaseactivity of IRAK4 may be modulated by affecting the binding of asubstrate of IRAK4 phosphorylation.

The compounds of the invention are used to treat or prevent inflammationrelated diseases. Disease states which can be treated by the methods andcompositions provided herein include, but are not limited to, cancer,autoimmune disease, viral disease, fungal disease,neurological/neurodegenerative disorders, arthritis, inflammation,anti-proliferative (e.g. ocular retinopathy), neuronal, alopecia,cardiovascular disease, graft rejection, inflammatory bowel disease,proliferation induced after medical procedures, including, but notlimited to, surgery, angioplasty, and the like. It is appreciated thatin some cases the cells may not be in a hyper- or hypoproliferationstate (abnormal state) and still require treatment. Thus, in oneembodiment, the invention herein includes application to cells orindividuals which are afflicted or may eventually become afflicted withany one of these disorders or states.

The compounds of this invention may be administered to mammals,including humans, either alone or, in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition, according to standard pharmaceutical practice. Thecompounds can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous and topicalroutes of administration.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, or alginic acid; binding agents, forexample starch, gelatin, polyvinyl-pyrrolidone or acacia, andlubricating agents, for example, magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to mask the unpleasant taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropylmethyl-cellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, cellulose acetate buryrate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of sterile injectableaqueous solutions. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulation.

The injectable solutions or microemulsions may be introduced into apatient's blood-stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

When a composition according to this invention is administered into ahuman subject, the daily dosage will normally be determined by theprescribing physician with the dosage generally varying according to theage, weight, and response of the individual patient, as well as theseverity of the patient's symptoms.

The dosage regimen utilizing the compounds of the instant invention canbe selected in accordance with a variety of factors including type, age,weight, sex; the route of administration; the renal and hepatic functionof the patient; and the particular compound or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to treat, forexample, to prevent, inhibit (fully or partially) or arrest the progressof the disease. For example, compounds of the instant invention can beadministered in a total daily dose of up to 10,000 mg. Compounds of theinstant invention can be administered once daily (QD), or divided intomultiple daily doses such as twice daily (BID), and three times daily(TID). Compounds of the instant invention can be administered at a totaldaily dosage of up to 10,000 mg, e.g., 2,000 mg, 3,000 mg, 4,000 mg,6,000 mg, 8,000 mg or 10,000 mg, which can be administered in one dailydose or can be divided into multiple daily doses as described above.

For example, compounds of the instant invention can be administered in atotal daily dose of up to 1,000 mg. Compounds of the instant inventioncan be administered once daily (QD), or divided into multiple dailydoses such as twice daily (BID), and three times daily (TID). Compoundsof the instant invention can be administered at a total daily dosage ofup to 1,000 mg, e.g., 200 mg, 300 mg, 400 mg, 600 mg, 800 mg or 1,000mg, which can be administered in one daily dose or can be divided intomultiple daily doses as described above.

In addition, the administration can be continuous, i.e., every day, orintermittently. The terms “intermittent” or “intermittently” as usedherein means stopping and starting at either regular or irregularintervals. For example, intermittent administration of a compound of theinstant invention may be administration one to six days per week or itmay mean administration in cycles (e.g. daily administration for two toeight consecutive weeks, then a rest period with no administration forup to one week) or it may mean administration on alternate days.

In addition, the compounds of the instant invention may be administeredaccording to any of the schedules described above, consecutively for afew weeks, followed by a rest period. For example, the compounds of theinstant invention may be administered according to any one of theschedules described above from two to eight weeks, followed by a restperiod of one week, or twice daily at a dose of 100-500 mg for three tofive days a week. In another particular embodiment, the compounds of theinstant invention may be administered three times daily for twoconsecutive weeks, followed by one week of rest.

Any one or more of the specific dosages and dosage schedules of thecompounds of the instant invention, may also be applicable to any one ormore of the therapeutic agents to be used in the combination treatment(hereinafter referred to as the “second therapeutic agent”).

Moreover, the specific dosage and dosage schedule of this secondtherapeutic agent can further vary, and the optimal dose, dosingschedule and route of administration will be determined based upon thespecific second therapeutic agent that is being used.

Of course, the route of administration of the compounds of the instantinvention is independent of the route of administration of the secondtherapeutic agent. In an embodiment, the administration for a compoundof the instant invention is oral administration. In another embodiment,the administration for a compound of the instant invention isintravenous administration. Thus, in accordance with these embodiments,a compound of the instant invention is administered orally orintravenously, and the second therapeutic agent can be administeredorally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form.

In addition, a compound of the instant invention and second therapeuticagent may be administered by the same mode of administration, i.e. bothagents administered e.g. orally, by IV. However, it is also within thescope of the present invention to administer a compound of the instantinvention by one mode of administration, e.g. oral, and to administerthe second therapeutic agent by another mode of administration, e.g. IVor any other ones of the administration modes described hereinabove.

The first treatment procedure, administration of a compound of theinstant invention, can take place prior to the second treatmentprocedure, i.e., the second therapeutic agent, after the treatment withthe second therapeutic agent, at the same time as the treatment with thesecond therapeutic agent, or a combination thereof. For example, a totaltreatment period can be decided for a compound of the instant invention.The second therapeutic agent can be administered prior to onset oftreatment with a compound of the instant invention or followingtreatment with a compound of the instant invention.

The instant compounds are also useful in combination with othertherapeutic agents. Combinations of the presently disclosed compoundswith therapeutic agents are within the scope of the invention. A personof ordinary skill in the art would be able to discern which combinationsof agents would be useful based on the particular characteristics of thedrugs and the pathologies involved. The instant compounds are alsouseful in combination with known therapeutic agents.

The instant compounds are useful in combination with a knownanti-inflammatory agent. In one embodiment, the anti-inflammatory agentis a nonsteroidal anti-inflammatory drug (NSAID). In one embodiment, theNSAID is selected from the group consisting of salicylates,indomethacin, flurbiprofen, diclofenac, ketorolac, naproxen, piroxicam,tebufelone, ibuprofen, etodolac, nabumetone, tenidap, alcofenac,antipyrine, aminopyrine, dipyrone, aminopyrone, phenylbutazone,clofezone, oxyphenbutazone, prenazone, apazone, benzydamine, bucolome,cinchophen, clonixin, ditrazol, epirizole, fenoprofen, floctafenin,flufenamic acid, glaphenine, indoprofen, ketoprofen, loxoprofen,meclofenamic acid, mefenamic acid, niflumic acid, phenacetin,salidifamides, sulindac, suprofen, tolmetin, a pharmaceuticallyacceptable salt thereof, and a mixture thereof.

In another embodiment, the NSAID is a selective COX-2 inhibitor. Forpurposes of this specification NSAID's which are selective inhibitors ofCOX-2 are defined as those which possess a specificity for inhibitingCOX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays.Such compounds include, but are not limited to those disclosed in U.S.Pat. No. 5,474,995, U.S. Pat. No. 5,861,419, U.S. Pat. No. 6,001,843,U.S. Pat. No. 6,020,343, U.S. Pat. No. 5,409,944, U.S. Pat. No.5,436,265, U.S. Pat. No. 5,536,752, U.S. Pat. No. 5,550,142, U.S. Pat.No. 5,604,260, U.S. Pat. No. 5,698,584, U.S. Pat. No. 5,710,140, WO94/15932, U.S. Pat. No. 5,344,991, U.S. Pat. No. 5,134,142, U.S. Pat.No. 5,380,738, U.S. Pat. No. 5,393,790, U.S. Pat. No. 5,466,823, U.S.Pat. No. 5,633,272, and U.S. Pat. No. 5,932,598, all of which are herebyincorporated by reference.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to: parecoxib, CELEBREX® and BEXTRA® or a pharmaceuticallyacceptable salt thereof.

Those skilled in the art will realize that the term “cancer” to be thename for diseases in which the body's cells become abnormal and dividewithout control.

Cancers that may be treated by the compounds, compositions and methodsof the invention include, but are not limited to: Cardiac: sarcoma(angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma,rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma(squamous cell, undifferentiated small cell, undifferentiated largecell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma)colorectal; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma), breast; Hematologic: blood (myeloidleukemia [acute and chronic], acute lymphoblastic leukemia, chroniclymphocytic leukemia, myeloproliferative diseases, multiple myeloma,myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma[malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi,lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands:neuroblastoma. Thus, the term “cancerous cell” as provided herein,includes a cell afflicted by any one of the above-identified conditions.

In one embodiment, cancers that may be treated by the compounds,compositions and methods of the invention include, but are not limitedto: lung cancer, pancreatic cancer, colon cancer, colorectal cancer,myeloid leukemias, acute myelogenous leukemia, chronic myelogenousleukemia, chronic myelomonocytic leukemia, thyroid cancer,myelodysplastic syndrome, bladder carcinoma, epidermal carcinoma,melanoma, breast cancer, prostate cancer, head and neck cancers, ovariancancer, brain cancers, cancers of mesenchymal origin, sarcomas,tetracarcinomas, neuroblastomas, kidney carcinomas, hepatomas,non-Hodgkin's lymphoma, multiple myeloma, and anaplastic thyroidcarcinoma.

In another embodiment, cancers that may be treated by the compounds,compositions and methods of the invention include, but are not limitedto: breast, prostate, colon, colorectal, lung, brain, testicular,stomach, pancrease, skin, small intestine, large intestine, throat, headand neck, oral, bone, liver, bladder, kidney, thyroid and blood.

In another embodiment, cancers that may be treated by the compounds,compositions and methods of the invention include breast, prostate,colon, ovary, endometrium and thyroid.

In another embodiment, cancers that may be treated by the compositionsand methods of the invention include acute myeloid leukemia (AML),liposarcoma, colorectal cancer, gastric cancer and melanoma.

In a further embodiment, cancers that may be treated by the compositionsand methods of the invention include hematological malignancies, forexample acute myeloid leukemia.

In a further embodiment, cancers that may be treated by the compositionsand methods of the invention include acute lymphoblastic leukemia (ALL),lymphoma, lung, breast and glioblastoma.

The compounds of the invention are also useful in preparing a medicamentthat may be useful in treating cancer. In one embodiment, the compoundsof the invention are for the potential treatment of cancer.

The compounds of the invention may be useful to the treatment of avariety of cancers, including, but not limited to: carcinoma, including,but not limited to, of the bladder, breast, colon, rectum, endometrium,kidney, liver, lung, head and neck, esophagus, gall bladder, cervix,pancreas, prostrate, larynx, ovaries, stomach, uterus, sarcoma andthyroid cancer; hematopoietic tumors of the lymphoid lineage, includingleukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia,acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkinslymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle celllymphoma, myeloma, and Burkett's lymphoma; hematopoetic tumors ofmyeloid lineage, including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukemia; tumors ofmesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumorsof the central and peripheral nervous system, including astrocytoma,neuroblastoma, glioma, and schwannomas; and other tumors, includingmelanoma, skin (non-melanomal) cancer, mesothelioma (cells), seminoma,teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma,thyroid follicular cancer and Kaposi's sarcoma.

The compounds of the invention may be useful for the treatment ofactivated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), chroniclymphocytic leukemia (CLL) and Waldenström's Macroglobulinemia.

The instant compounds are useful in combination with a known anti-canceragent. Combinations of the presently disclosed compounds withanti-cancer agents are within the scope of the invention. Examples ofsuch anti-cancer agents can be found in Cancer Principles and Practiceof Oncology by V. T. Devita and S. Hellman (editors), 6th edition (Feb.15, 2001), Lippincott Williams & Wilkins Publishers. A person ofordinary skill in the art would be able to discern which combinations ofagents would be useful based on the particular characteristics of thedrugs and the cancer involved. Such agents include the following:estrogen receptor modulators, androgen receptor modulators, retinoidreceptor modulators, cytotoxic/cytostatic agents, antiproliferativeagents, prenyl-protein transferase inhibitors, HMG-CoA reductaseinhibitors and other angiogenesis inhibitors, HIV protease inhibitors,reverse transcriptase inhibitors, inhibitors of cell proliferation andsurvival signaling, bisphosphonates, aromatase inhibitors, siRNAtherapeutics, γ-secretase inhibitors, agents that interfere withreceptor tyrosine kinases (RTKs) and agents that interfere with cellcycle checkpoints.

In one embodiment, the anti-cancer agent is selected from the groupconsisting of abarelix (Plenaxis Depot®); aldesleukin (Prokine®);Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin(Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine(Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®);asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®);bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin(Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®);busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine(Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®);carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (GliadelWafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil(Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®);clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®);cyclophosphamide (Cytoxan Injection®); cyclophosphamide (CytoxanTablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®);dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®);Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DanuoXome®);daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin(Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®);docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin(Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®);doxorubicin liposomal (Doxil®); dromostanolone propionate(Dromostanolone®); dromostanolone propionate (masterone Injection®);Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®);Epoetin alfa (Epogen®); erlotinib (Tarceva®); estramustine (Emcyt®);etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®);exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine(intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU(Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine(Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (ZoladexImplant®); goserelin acetate (Zoladex®); histrelin acetate (HistrelinImplant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®);idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate(Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (IntronA®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole(Ferrara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate(Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®);meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate(Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP(Purinethol®); mesna (Mesnex®); mesna (Mesnex Tabs®); methotrexate(Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®);mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolonephenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab(Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel(Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles(Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase(Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim(Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimersodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®);Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim (Leukine®);Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®);sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®);temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone(Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®);topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®);Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®);tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®);valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®);vinorelbine (Navelbine®); zoledronate (Zometa®) and vorinostat(Zolinza®); a pharmaceutically acceptable salt thereof, and a mixturethereof.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

Further included within the scope of the invention is a method fortreating an inflammatory disease which comprises administering to amammal in need thereof a therapeutically effective amount of a compoundof the instant invention.

Further included within the scope of the invention is a method fortreating an inflammatory disease which comprises administering to amammal in need thereof a therapeutically effective amount of a compoundof the instant invention wherein the inflammatory disease is selectedfrom rheumatoid arthritis, inflammatory bowel disease and cancer.

The compounds of the instant invention are useful for the treatmentand/or reducing the severity of rheumatoid arthritis.

The compounds of the instant invention are useful for the treatmentand/or reducing the severity of inflammatory bowel disease.

The compounds of the instant invention are useful for the treatmentand/or reducing the severity of lupus.

The compounds of the instant invention are useful for the treatmentand/or reducing the severity of cancer.

The compounds of the instant invention are useful for the treatment ofrheumatoid arthritis.

The compounds of the instant invention are useful for the treatment ofinflammatory bowel disease.

The compounds of the instant invention are useful for the treatment oflupus.

The compounds of the instant invention are useful for the treatment ofcancer.

Further included within the scope of the invention is a method oftreating an inflammatory disease which comprises administering atherapeutically effective amount of a compound of the instant inventionin combination with a second therapeutic agent.

Further included within the scope of the invention is a method oftreating an inflammatory disease which comprises administering atherapeutically effective amount of a compound of the instant inventionin combination with a second therapeutic agent, wherein the secondtherapeutic agent is selected from an anti-cancer agent and ananti-inflammatory agent.

Abbreviations used in the description of the chemistry and in theExamples that follow are:

-   2nd Gen. Precatalyst cataCXium®    chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)-   2nd Gen. Precatalyst X-Phos Chloro    (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)-   3rd Gen X-Phos Precatalys    (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)    methanesulfonate-   Ac Acetyl-   ACN or MeCN acetonitrile-   AcOH or HOAc acetic acid-   APCI atmospheric-pressure chemical ionization-   aq aqueous-   Bn benzyl-   Boc or BOC tert-butoxycarbonyl-   Brettphos    2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl-   Bu butyl-   Bz benzoyl-   calc'd calculated-   cBu cyclobutyl-   Cbz benyzloxycarbonyl-   CDCl₃ chloroform-d-   CHCl₃ Chloroform-   cHep cycloheptyl-   cHex cyclohexyl-   cPen cyclopentyl-   cPr cyclopropyl-   DAST (diethylamino)sulfur trifluoride-   dba dibenzylideneacetone-   DBU 1,8-diazabicycloundec-7-ene-   DCE 1,2-dichloroethane-   DCM dichloromethane-   DIBAL or Dibal-H diisobutylaluminum hydride-   DIEA or Hünig's base N,N-diisopropylethylamine-   DMA 1,2-dimethylacetamide-   DMAP 4-dimethylaminopyridine-   DMEA Dimethylethylamine-   DMSO Dimethylsulfoxide-   DMF dimethylformamide-   DMP Dess-Martin periodinane    (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one-   DMSO dimethyl sulfoxide-   dppf 1,1′-bis(diphenylphosphino)ferrocene-   DTT dithiothreitol-   EDC 1-ethyl-3-(3-dimethylaminopropy)carbodiimide-   EDTA ethylenediamine tetraacetic acid-   ESI electrospray ionization-   Et ethyl-   EtOH ethanol-   EtOAc ethyl acetate-   g grams-   GST glutathione S-transferase-   h hour-   HATU N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium    hexafluorophosphate-   HCl hydrochloric acid-   HMDS 1,1,1,3,3,3-hexamethyldisilazane-   HOBt 1-hydroxybenzotriazole-   HPLC high-performance liquid chromatography-   IPA or iPrOH isopropanol-   iPr isopropyl-   LC liquid chromatography-   LCMS liquid chromatography mass spectrometry-   LDA lithium diisopropylamide-   M molar-   mCPBA m-choroperoxybenzoic acid-   Me methyl-   MeOH methanol-   mg milligrams-   min minute-   μL microliters-   mL milliliters-   mmol millimoles-   MS mass spectrometry-   Ms methanesulfonyl (mesyl)-   MTBE methyl tert-butyl ether-   NBS N-bromosuccinimide-   NMR nuclear magnetic resonance spectroscopy-   OAc Acetate-   obsv'd observed-   Pd(PPh₃)₄ palladium(0) tetrakis-triphenylphosphine-   Pd(dppf)Cl₂1,1′-bis(diphenylphosphino)ferrocene]dichloro    palladium(II)-   Ph phenyl-   (PinB)₂ 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)-   POCl₃ phosphorous oxychloride-   Pr propyl-   PS polystyrene-   rac racemic mixture-   RT or rt room temperature (ambient, about 25° C.)-   sat saturated-   SFC supercritical fluid chromatography-   Si-DPP-Pd SiliaCat®DPP-Pd-   S-phos 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-   T3P Propylphosphonic anhydride-   TBAF tert-butyl ammonium fluoride-   TBDPS tert-butyl diphenyl silyl-   TBS or TBDMS tert-butyldimethyl silyl-   TBSCl tert-butyldimethylsilyl chloride-   tBu tert-butyl-   tBu X-phos 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl-   TEA triethylamine (Et₃N)-   TFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   THF tetrahydrofuran-   TLC thin layer chromatography-   TMS trimethylsilyl-   Tris tris(hydroxymethyl)aminomethane-   Ts toluenesulfonyl (tolyl)-   TSA p-toluenesulfonic acid-   X-phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl-   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

General Synopsis of Reaction Schemes

The following General Reaction Schemes, Schemes 1 to 8, provide usefuldetails for preparing the instant compounds. The requisite intermediatesare in some cases commercially available or can be prepared according toliterature procedures. The illustrative General Reaction Schemes beloware not limited by the compounds listed or by any particularsubstituents employed for illustrative purposes. Substituent labeling(i.e. R groups) as shown in the Reaction Schemes do not necessarilycorrelate to that used in the claims and often, for clarity, a singlesubstituent is shown attached to the compound where multiplesubstituents are allowed under the definitions of Formula I hereinabove.

Compounds of formula IV are prepared by the reaction of4-chloroquinazolines (II) with substituted diamines (III) via S_(N)Arconditions followed by acidic deprotection of the Boc protecting group.Additionally, compounds of formula VI are prepared by the reaction of4-chloroquinazolines (II) with the desired amines or alcohols (V) viaS_(N)Ar conditions.

Compounds of formula VI are also obtained by the reductive amination ofcyclohexanones (VIII) with substituted amines (IX). Cyclohexanones(VIII) are prepared by the reaction of 4-chloroquinazolines (II) withthe desired substituted 4-aminocyclohexanones (VII) via S_(N)Arconditions. Substituted 4-chloroquinazolines (II) are prepared fromsubstituted 4-quinazolinones (I) by chlorination with POCl₃.

Compounds of formula XII are prepared by the reaction of4-chloroquinazolines (XI) with desired amines or alcohols (V) viaS_(N)Ar conditions. Substituted 4-chloroquinazolines (XI) are preparedfrom substituted 4-chloroquinazolin-6-ols (X) via alkylating conditions.

Compounds of formula XIV are prepared from substitued quinazolines(XIII) by hydrolysis of the nitrile. Substituted quinazolines (XIII) areprepared according to Scheme 2.

Compounds of formula XVI are prepared from substitued quinazolines (XV)by palladium-mediated cyanation. Substituted quinazolines (XV) areprepared according to Scheme 1.

Compounds of formula XIV are prepared by the reaction of4-chloroquinazolines (II) with substituted cyclohexylamines (XVIII) viaS_(N)Ar conditions. Substituted cyclohexylamines (XVIII) are prepared bythe reductive amination of protected 4-aminocyclohexanones (XVII) withsubstituted amines (IX) followed by acidic deprotection of the Bocprotecting group.

Compounds of formula XIX are prepared from piperazines (XXI) byamidation conditions. Piperazines (XXI) are prepared by acidicdeprotection of 4-aminoquinazolines (XX). 4-Aminoquinazolines areprepared according to the reductive amination route in Scheme 1.

Compounds of formula XXIV are prepared by the reductive amination ofcyclohexanones (VIII) with substituted amines (IX). Cyclohexanones(VIII) are obtained by acitic deprotection of protected4-aminocyclohexanones (XVII) followed by reaction with4-chloroquinazolines (II) via S_(N)Ar conditions.

Compounds of formula XXX are prepared by the reductive amination ofcyclohexanones (XXIX) with substituted amines (IX). Cyclohexanones(XXIX) are obtained from acetic deprotection of cyclic ketals (XXVIII).Cyclic ketals are prepared by the reaction of 4-chloroquinazolines (II)with cyclohexylamine (XXVII) via S_(N)Ar conditions. Cyclohexylamine(XXVII) is prepared by reduction of imine (XXVI) followed byhydrogenolysis of the benzyl group Imine (XXVI) is obtained fromcondensation of cyclohexanone (XXV) with benzylamine.

Intermediate 1-1

4-((4-oxocyclohexyl)amino)quinazoline-6-carbonitrile (Scheme 1)

4-Chloroquinazoline-6-carbonitrile (1.10 g, 5.78 mmol),4-aminocyclohexanone hydrochloride (1.30 g, 8.66 mmol), DIEA (8.07 mL,46.2 mmol), and DMA (60 mL) were added to a round bottom flask. Thecontents of the flask were allowed to stir for 4 h at rt. The reactionmixture was concentrated under reduced pressure. MeOH was addedresulting in formation of a precipitate, which was collected by vacuumfiltration and dried under reduced pressure to afford the titlecompound. MS: 267 (M+1). ¹H NMR (600 MHz, dmso) δ 8.94 (s, 1H), 8.59 (s,1H), 8.39 (s, 1H), 8.06 (d, J=8.6, 1H), 7.76 (d, J=8.6, 1H), 4.71-4.61(m, 1H), 2.58-2.50 (m, 2H), 2.30 (d, J=14.7, 2H), 2.22-2.15 (m, 2H),1.89-1.79 (m, 2H).

Intermediate 2-1

6-bromo-4-chloro-5-methylquinazoline (Scheme 1)

Phosphorus oxychloride (5.07 ml, 54.4 mmol) and N,N-diisopropylethylamie(0.095 mL, 0.540 mmol) were added to a microwave vial containing6-bromo-5-methylquinazolin-4-ol (0.13 g, 0.54 mmol). The vial was sealedand then heated at 80° C. for 18 h. Upon completion of the reaction, thesolvent was removed under reduced pressure. The residue was furtherdried by addition of toluene, followed by further solvent removal underreduced pressure. The title compound was obtained without furtherpurification. MS: 256/258 (M+1).

Intermediate 3-1

[(4-chloroquinazolin-6-yl)oxy]acetonitrile (Scheme 2)

Bromoacetonitrile (0.075 ml, 1.107 mmol) was added to a solution of4-chloroquinazolin-6-ol (0.1 g, 0.554 mmol) and cesium carbonate (0.361g, 1.107 mmol) in DMF (2.77 mL), all under an atmosphere of argon. Thereaction was stirred for 3 h at rt. The reaction was diluted with waterand extracted with EtOAc (3×), the combined organic layers were thenwashed with water and brine, dried over anhydrous sodium sulfate,filtered and the material was used without further purification. MS: 220(M+1).The following intermediates in Table 1 were prepared in an analogousmanner to that described for Intermediate 3-land in general scheme 2.

TABLE 1 Intermediate Number Structure Chemical Name MS (M + 1) 3-2

4[(4-chloroquinazolin- 6-yl)oxy]butanenitrile Calc'd 248.0, found 2483-3

2-[(4-chloroquinazoin- 6-yl)oxy]acetamide Calc'd 238.0, found 238

Intermediate 4-1

(1S,6R)-5-(morpholin-4-yl)bicyclo[4.1.0]heptan-2-amine (Scheme 5)

A 20 mL scintillation vial was charged with morpholine (0.043 mL, 0.488mmol) and 1,2-dichloroethane (4.5 mL). tert-Butyl((1S,2S,6R)-5-oxobicyclo[4.1.0]heptan-2-yl)carbamate (100 mg, 0.444mmol) and acetic acid (0.127 mL, 2.22 mmol) were added and the reactionmixture was stirred at rt for 5 min. Sodium triacetoxyborohydride (329mg, 1.55 mmol) was added and the reaction mixture was stirred at rt foran additional 16 h. Desired product formation was confirmed by LCMSanalysis. The mixture was diluted with dichloromethane (5 mL), washedwith aqueous sodium hydrogen carbonate (saturated, 2×5 mL), dried(MgSO₄), filtered and the solvent evaporated under reduced pressure. Theresulting residue was taken up in a mixture of dioxane (1 mL) and water(0.2 mL). A solution of 4 N hydrochloric acid (2 mL, 8 mmol) in dioxanewas added and the resulting mixture stirred at rt for 1 h. Fullhydrolysis was confirmed by LCMS analysis. The reaction mixture wasconcentrated, taken up in water/acetonitrile (1:1, 5 mL) andlyophillized overnight to afford(1S,6R)-5-(morpholin-4-yl)bicyclo[4.1.0]heptan-2-amine. MS: 197 (M+1).

Intermediate 5-1

4-{[(7S,8S or7R,8R)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl]amino}quinazoline-6-carbonitrileand 4-{[(7S,8R or7R,8S)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl]amino}quinazoline-6-carbonitrile(Scheme 8) Step 1:N-(7-Methyl-1,4-dioxaspiro[4.5]decan-8-ylidene)-1-phenylmethanamine

A solution of titanium tetrachloride in DCM (1M, 5.88 mL, 5.88 mmol) wasadded dropwise to a stirred ice-cooled solution of triethylamine (9.83mL, 70.5 mmol) and benzylamine (1.54 mL, 14.1 mmol) in DCM (10 mL) underan inert atmosphere. The reaction was warmed to ambient temperature andthen refluxed. A solution of 7-methyl-1,4-dioxaspiro[4.5]decan-8-one(2.00 g, 11.8 mmol) in DCM (10 mL) was added and the reaction mixturewas refluxed for an additional 16 hours. The reaction was cooled to roomtemperature and then diluted with diethyl ether (20 mL). The formedprecipitate was filtered off and washed through with diethyl ether. Thefiltrate was concentrated and the resulting brown oil taken forward tothe next step. MS: 260 (M+1).

Step 2: N-Benzyl-7-methyl-1,4-dioxaspiro[4.5]decan-8-amine

To a solution ofN-(7-methyl-1,4-dioxaspiro[4.5]decan-8-ylidene)-1-phenylmethanamine(3.11 g, 12.0 mmol) in ethanol (30 mL) cooled to −78° C., was addedsodium borohydride (0.227 g, 6.00 mmol). The reaction mixture wasstirred for 30 minutes and then warmed to −20° C. Saturated sodiumpotassium tartrate (5 mL) was added and the ethanolic solutionconcentrated. The resulting residue was diluted with water, basifiedwith sodium bicarbonate solution and extracted with ethyl acetate (2×10mL). The organic layer was washed with brine (2×10 mL), dried (MgSO₄),filtered and the solvent was evaporated under reduced pressure. Theresulting residue was purified by column chromatography on silica gelISCO; 80 g prepacked, (0-60% hexanes/ethyl acetate) to afford a mixtureof the cis- and trans-diastereomers. MS: 262 (M+1).

Step 3: 7-Methyl-1,4-dioxaspiro[4.5]decan-8-amine

To a 100 mL round bottom flask charged withN-benzyl-7-methyl-1,4-dioxaspiro[4.5]decan-8-amine (0.678 g, 2.59 mmol)and methanol (20 mL) was added palladium hydroxide on carbon (0.091 g,0.130 mmol). The flask was evacuated and back-filled with hydrogen gasusing a balloon. This procedure was carried out another two times andthe reaction mixture was stirred under a hydrogen atmosphere for 16hours. The palladium was filtered by passing through a plug of celiteand washing through with methanol. The filtrate was concentrated toafford the title compound. MS: 172 (M+1).

Step 4: 4-{[(7S,8S or7R,8R)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl]amino}quinazoline-6-carbonitrileand 4-{[(7S,8R or7R,8S)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl]amino}quinazoline-6-carbonitrile

A 20 mL scintillation vial was charged with4-chloroquinazoline-6-carbonitrile (0.275 g, 1.45 mmol),7-methyl-1,4-dioxaspiro[4.5]decan-8-amine (0.422 g, 2.03 mmol) and DMA(15 mL). DIEA (2.03 mL, 11.6 mmol) was added, the vial was capped andthe contents stirred at room temperature for 16 hours. The volatileswere removed in vacuo, the resulting residue diluted withdichloromethane/iPrOH (10:1, 10 mL), washed with aqueous ammoniumchloride (saturated, 2×10 mL), dried (MgSO₄), filtered and the solventwas evaporated under reduced pressure. The resulting residue waspurified by column chromatography on silica gel ISCO; 24 g prepacked,(0-66% hexanes/ethyl acetate) to afford 4-{[(7S,8S or7R,8R)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl]amino}quinazoline-6-carbonitrile,MS: 325 (M+1) ¹H NMR (600 MHz, CDCl₃): δ 8.69 (s, 1H); 8.18 (s, 1H);7.92-7.87 (m, 2H); 6.00 (br s, 1H); 4.67-4.62 (m, 1H); 4.04-3.94 (m,4H); 2.33-2.29 (m, 1H); 2.06-2.03 (m, 1H); 1.93-1.86 (m, 1H); 1.81 (dd,J=13.9, 4.3 Hz, 1H); 1.72 (dd, J=10.0, 4.7 Hz, 2H); 1.64 (t, J=12.7 Hz,1H); 1.01 (d, J=7.0 Hz, 3H) and 4-{[(7S,8R or7R,8S)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl]amino}quinazoline-6-carbonitrile.MS: 325 (M+1) ¹H NMR (600 MHz, CDCl₃): δ 8.67 (s, 1H); 8.27 (br s, 1H);7.92 (s, 1H); 7.87 (d, J=8.5 Hz, 1H); 4.18-4.13 (m, 1H); 3.99-3.93 (m,4H); 2.13-2.09 (m, 1H); 1.96 (br s, 1H); 1.87 (dt, J=13.5, 3.5 Hz, 1H);1.85-1.80 (m, 1H); 1.75 (td, J=13.5, 4.1 Hz, 1H); 1.64 (q, J=12.8 Hz,1H); 1.53 (t, J=13.0 Hz, 1H): 0.99 (d, J=6.6 Hz, 3H).

Example 1-1

4-[(Trans-4-aminocyclohexyl)amino]quinazoline-6-carbonitrile (Scheme 1)Step 1: tert-butyl{trans-4-[(6-cyanoquinazolin-4-yl)amino]cyclohexyl}carbamate

4-Chloroquinazoline-6-carbonitrile (50 mg, 0.264 mmol), Cs₂CO₃ (301 mg,0.923 mmol), and tert-butyl ((trans)-4-aminocyclohexyl)carbamatebis-hydrochloride (91.0 mg, 0.316 mmol) were added to a vial, and thenDMF (2 mL) was added. The vial was sealed and stirred overnight at rt.Water was added resulting in formation of a precipitate, which wascollected via vacuum filtration, and washed with diethyl ether. Thecollected solids were dried under reduced pressure to afford the titlecompound. MS: 368 (M+1).

Step 2: 4-[(trans-4-aminocyclohexyl)amino]quinazoline-6-carbonitrile

Tert-butyl((trans)-4-((6-cyanoquinazolin-4-yl)amino)cyclohexyl)carbamate (22 mg,0.060 mmol) was weighed directly into a vial. The contents of the vialwere dissolved in dichloromethane (1 mL), and then 4N HCl in dioxane(200 μl, 0.800 mmol) was added. The vial was sealed and its contentswere stirred for 2 h at rt. The reaction mixture was concentrated underreduced pressure. The residue was dissolved in DMSO (1 mL), filtered,and purified by mass triggered reverse phase HPLC (ACN/water with 0.1%NH₄OH modifier) to afford the title compound. MS: 268 (M+1). 1H NMR (600MHz, dmso) δ 8.90 (s, 1H), 8.51 (s, 1H), 8.21 (d, J=7.4, 1H), 8.01 (d,J=8.5, 1H), 7.72 (d, J=8.6, 1H), 4.15-4.01 (m, 1H), 2.63-2.54 (m, 1H),1.96-1.86 (m, 2H), 1.86-1.75 (m, 2H), 1.44-1.34 (m, 2H), 1.21-1.09 (m,2H).The following example in Table 2 was prepared in an analogous manner tothat described in Example 1 and in general scheme 1.

TABLE 2 Example # Structure Chemical Name MS (M + 1) 1-2

trans-N-(6- bromoquinazolin-4- yl)cyclohexane-1,4- diamine Calc'd 321.0,found 321/323

Example 2-1

6-Bromo-4-{[trans-4-(morpholin-4-yl)cyclohexyl]oxy}quinazoline (Scheme1)

Trans-4-morpholinocyclohexanol (0.134 g, 0.723 mmol) was dissolved inTHF (10.95 ml) and added to a slurry of 6-bromo-4-chloroquinazoline(0.16 g, 0.657 mmol) in N,N-dimethylformamide (0.349 mL). The reactionwas cooled to 0° C. and sodium hydride (0.053 g, 1.31 mmol) was added tothe reaction mixture at 0° C. and the reaction was allowed to stir at rtfor 18 h. The reaction was quenched with saturated aqeuous sodiumbicarbonate and the aqueous layer was extracted with 25% IPA/CHCl₃ (2×),dried over anhydrous sodium sulfate, filtered and purified by masstriggered reverse phase HPLC (ACN/water with 0.1% NH₄OH modifier) toafford the title compound. MS: 392/394 (M+1). ¹H NMR (600 MHz, dmso) δ8.78 (s, 1H), 8.21 (d, J=2.2, 1H), 8.04 (dd, J=2.3, 8.9, 1H), 7.82 (d,J=8.9, 1H), 5.26-5.17 (m, 1H), 3.57-3.51 (m, 4H), 2.46-2.42 (m, 4H),2.30-2.22 (m, 1H), 2.21-2.13 (m, 2H), 1.92-1.83 (m, 2H), 1.62-1.50 (m,2H), 1.46-1.33 (m, 2H).

Example 2-2

6-Bromo-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine (Scheme1)

To a solution of (trans)-4-morpholinocyclohexanamine bis-hydrochloride(50.00 g, 226.51 mmol) and 6-bromo-4-chloroquinazoline (66.18 g, 271.81mmol) in DMF (600 mL) was added a solution of TEA (137.52 g, 1.36 mol)drop-wise at rt under N₂. The reaction mixture was heated to 90° C. for16 h, and then cooled to rt, poured into ice/water and filtered. Thefiltered cake washed with water and dried to give the title compound asa solid. MS: 391/393 (M+1). ¹H NMR (600 MHz, cd3od) δ 8.43 (d, J=2.1,1H), 8.41 (s, 1H), 7.85 (dd, J=2.1, 8.9, 1H), 7.57 (d, J=8.9, 1H),4.22-4.12 (m, 1H), 3.74-3.65 (m, 4H), 2.66-2.55 (m, 4H), 2.36-2.25 (m,1H), 2.19-2.09 (m, 2H), 2.09-2.00 (m, 2H), 1.54-1.38 (m, 4H).The following examples in Table 3 were prepared in an analogous mannerof those described in Example 2-1 and Example 2-2 and in general schemes1, 2 and 5 using intermediates of general structure II and XI which wereeither commercial or prepared as described herein.

TABLE 3 Example # Structure Chemical Name MS (M + 1) 2-3

trans-N′-(6,7- dimethoxyquinazolin-4- yl)-N,N- dimethylcyclohexane-1,4-diamine Calc'd 331.0, found 331 2-4

trans-N′-(6,7- difluoroquinazolin-4-yl)- N,N- dimethylcyclohexane-1,4-diamine Calc'd 307.0, found 307 2-5

4-{[trans-4- (dimethylamino)cyclohexyl] amino}quinazoline-6-carbonitrile Calc'd 296.0, found 296 2-6

trans-N′-(6- bromoquinazolin-4-yl)- N,N- dimethylcyclohexane-1,4-diamine Calc'd 349.0, found 349/351 2-7

4-{[trans-4-(morpholin- 4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 338.0, found 338 2-8

6-methoxy-N-[trans-4- (morpholin-4- yl)cyclohexyl]quinazolin- 4-amineCalc'd 343.0, found 343 2-9

6-fluoro-N-[trans-4- (morpholin-4- yl)cyclohexyl]quinazolin- 4-amineCalc'd 331.0, found 331 2-10

N-[trans-4-(morpholin-4- yl)cyclohexyl]-6-(propan- 2-yloxy)quinazolin-4-amine Calc'd 371.0, found 371 2-11

6-bromo-7-fluoro-N- [trans-4-(morpholin-4- yl)cyclohexyl]quinazolin-4-amine Calc'd 409.0, found 409/411 2-12

7-fluoro-6-methoxy-N- [trans-4-(morpholin-4- yl)cyclohexyl]quinazolin-4-amine Calc'd 361.0, found 361 2-13

6-chloro-N-[trans-4- (morpholin-4- yl)cyclohexyl]quinazolin- 4-amineCalc'd 347.0, found 347 2-14

trans-N′-(6- methoxyquinazolin-4-yl)- dimethylcyclohexane- 1,4-diamineCalc'd 301.0, found 301 2-15

[(4-{[trans-4- (dimethylamino)cyclohexyl] aminoiquinazolin-6-yl)oxy]acetonitrile Calc'd 326.0, found 326 2-16

4-[(4-{[trans-4- (dimethylamino)cyclohexyl] amino}quinazolin-6-yl)oxy]butanenitrile Calc'd 354.0, found 354 2-17

2-[(4-{[trans-4- (dimethylamino)cyclohexyl] amino}quinazolin-6-yl)oxy]acetamide Calc'd 344.0, found 344 2-18

4-{[(1S,6R)-5- (morpholin-4- yl)bicyclo[4.1.0]hept-2-yl]amino}quinazoline-6- carbonitrile Calc'd 350.0, found 350

Example 3-1

4-{[Trans-4-(azetidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile(Scheme 1)

4-((4-Oxocyclohexyl)amino)quinazoline-6-carbonitrile (25 mg, 0.094mmol), azetidine (9.00 mg, 0.158 mmol), and DMF (1 mL) were added to a2-dram vial. The vial was sealed and its contents were stirred for 6 hat 50° C. Sodium triacetoxyborohydride (29.8 mg, 0.141 mmol) was addedand the resulting reaction mixture was stirred overnight at 50° C. Theresidue was filtered and both isomers purified by mass triggered reversephase HPLC (ACN/water with 0.1% NH₄OH modifier). The desired isomer(faster eluting) was concentrated under reduced pressure to afford thetitle compound. MS: 308 (M+1). ¹H NMR (600 MHz, dmso) δ 8.97 (s, 1H),8.49 (s, 1H), 8.28 (d, J=6.5, 1H), 8.00 (d, J=8.6, 1H), 7.71 (d, J=8.5,1H), 4.23-4.13 (m, 1H), 3.03 (s, 4H), 2.18 (s, 1H), 1.91-1.83 (m, 2H),1.81-1.68 (m, 2H), 1.63-1.50 (m, 4H), 1.42-1.28 (m, 2H).The following examples in Table 4 were prepared in an analogous mannerto that described in Example 3-1 and general scheme 1.

TABLE 4 Example # Structure Chemical Name MS (M+1) 3-2

4-({cis or trans-4-[(3R or S)-3- (trifluoromethyl)piperidin- 1-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 404.0, found 4043-3

4-({cis or trans-4-[(3R or S)-3- (trifluoromethyl)piperidin- 1-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 404.0, found 4043-4

4-({cis or trans-4-[(3R or S)-3- (trifluoromethyl)piperidin- 1-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 404.0, found 4043-5

4-({cis or trans-4-[(3R or S)-3- (trifluoromethyl)piperidin- 1-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 404.0, found 4043-6

4-{[cis-4-(azetidin-1- yl)cyclohexyl]amino} quinazoline-6-carbonitrileCalc'd 308.0, found 308 3-7

4-{[trans-4-(2,3- dimethylmorpholin-4- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 366.0, found 366 3-8

4-{[cis-4-(2,3- dimethylmorpholin-4- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 366.0, found 366 3-9

4-({trans-4-[(2R,6S)-2,6- dimethylmorpholin-4- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 366.0, found 366 3-10

4-({trans-4-[4- (methylsulfonyl)piperidin- 1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 414.0, found 414 3-11

4-({trans-4-[(2R or 2S)- 2- (hydroxymethyl)morpholin- 4-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 368.0, found 3683-12

4-({trans-4-[(2R or 2S)- 2- (hydroxymethyl)morpholin- 4-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 368.0, found 3683-13

4-({trans-4-[3- (methylsulfonyl)pyrrolidin- 1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 400.0, found 400 3-14

4-({trans-4-[(2S,6S or 2R,6R)-2,6- dimethylmorpholin-4-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 366.0, found 3663-15

4-({trans-4-[2S,6S or 2R,6R)-2,6- dimethylmorpholin-4-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 366.0, found 3663-16

4-({trans-4-[(2S or 2R)- 2-methylmorpholin-4- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 352.0, found 352 3-17

4-({trans-4-[(2S or 2R)- 2-methylmorpholin-4- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 352.0, found 352 3-18

4-({trans-4-[(1S,4S)-2- oxa-5- azabicyclo[2.2.1]hept-5-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 350.0, found 3503-19

4-{[trans-4-(4- fluoropiperidin-1- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 354.0, found 354 3-20

4-({trans-4-[4- (methylsulfonyl)piperazin- 1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 415.0, found 415 3-21

4-({trans-4-[(2,2,2- trifluoroethyl)amino]cyclo-hexyl}amino)quinazoline- 6-carbonitrile Calc'd 350.0, found 350 3-22

4-({trans-4-[(2- methoxyethyl)amino] cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 326.0, found 326 3-23

4-{[trans-4- (cyclopropylamino)cyclo- hexyl]amino}quinazoline-6-carbonitrile Calc'd 308.0, found 308 3-24

4-({trans-4-[(4aS,7aS or 4aR,7aR)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)- yl]cyclohexyl}amino) quinazoline-6-carbonitrileCalc'd 378.0, found 378 3-25

4-{[trans-4-(hexahydro- 2H-pyrano[4,3-b]pyridin- 1(5H)-yl)cyclohexyl]amino} quinazoline-6-carbonitrile Calc'd 392.0, found 3923-26

4-{[trans-4-(4-oxa-7- azaspiro[2.5]oct-7- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 364.0, found 364 3-27

4-({trans-4-[2- (fluoromethyl)morpholin- 4- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 370.0, found 370 3-28

4-({trans-4-[(3S)-3- methylmorpholin-4- yl]cyclohexyl}amino)quinazolin-6-carbonitrile Calc'd 352.0, found 352 3-29

4-{[trans-4-(3- methoxyazetidin-1- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 338.0, found 338 3-30

4-{[trans-4-(4- methylpiperazin-1- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 351.0, found 351 3-31

4-({trans-4-[(3R)-3- methylmorpholin-4- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 352.0, found 352 3-32

4-({trans-4- [cyclopropyl(methyl) amino]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 322.0, found 322 3-33

4-{[trans-4-(3,3- difluoropiperidin-1- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 372.0, found 372 3-34

4-({trans-4-[(3S)-3- hydroxypyrrolidin-1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 338.0, found 338 3-35

4-{[trans-4-(3- fluoropiperidin-1- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 354.0, found 354 3-36

4-{[trans-4-(3-hydroxy- 3-methylpyrrolidin-1- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 352.0, found 352 3-37

4-({trans-4-[3- (morpholin-4-yl)azetidin- 1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 393.0, found 393 3-38

4-({trans-4-[(3R)-3- hydroxypyrrolidin-1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 338.0, found 338 3-39

4-{[trans-4-(hexahydro- 4H-furo[3,2-b]pyrrol-4- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 364.0, found 364 3-40

4-({trans-4-[(3R)-3- methoxypyrrolidin-1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 352.0, found 352 3-41

4-({trans-4-[(3R or 3S)- 3-(morpholin-4- ylmethyl)piperidin-1-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 435.0, found 4353-42

4-({trans-4-[(3R or 3S)- 3-(morpholin-4- ylmethyl)piperidin-1-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 435.0, found 4353-43

4-({trans-4-[4- (mopholin-4- ylmethyl)piperidin-1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 435.0, found 435 3-44

4-{[trans-4-(pyrrolidin- 1- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 322.0, found 322 3-45

tert-butyl 4-{trans-4-[(6- cyanoquinazolin-4- yl)amino]cyclohexyl}piperazine-1-carboxylate Calc'd 437.0, found 437 3-46

4-({trans-4-[3- (morpholin-4- ylmethyl)piperidin-1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 435.0, found 435 3-47

4-{[trans-4-(3-oxa-8- azabicyclo[3.2.1]oct-8- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 364.0, found 364 3-48

4-({trans-4-[(2R or 2S)- 2- (trifluoromethyl)morpholin- 4-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 406.0, found 4063-49

4-({trans-4-[(2R or 2S)- 2- (trifluoromethyl)morpholin- 4-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 406.0, found 4063-50

4-({trans-4-[(1R,5S)-8- oxa-3- azabicylco[3.2.1]oct-3-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 364.0, found 3643-51

4-{[trans-4-(2,2- dimethylmorpholin-4- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 366.0, found 366 3-52

4-({trans-4-[(3R)-3- (propan-2-yl)morpholin- 4- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 380.0, found 380 3-53

4-{[trans-4-(4,4- difluoroazepan-1- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 386.0, found 386 3-54

4-{[trans-4-(4,4- difluoropiperidin-1- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 372.0, found 372 3-55

4-{[trans-4-(3- hydroxypyrrolidin-1- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 338.0, found 338

Example 4-1

4-[(4-{[Trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)oxy]butanamide(Scheme 3)

Aqueous hydrogen peroxide (30%, 0.142 mL, 1.42 mmol) was added dropwiseto a solution of4-((4-(((trans)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)oxy)butanenitrile(0.05 g, 0.14 mmol) in aqueous ammonium hydroxide (0.2 M, 7.07 mL, 1.42mmol). The reaction was stirred for 18 h at rt. The reaction wasfiltered, and the solvent removed under reduced pressure. The materialwas purified by mass triggered reverse phase HPLC (ACN/water with 0.1%TFA modifier) to afford the title compound as the TFA salt. MS: 372(M+1). ¹H NMR (600 MHz, dmso) δ 9.67 (s, 1H), 9.57 (d, J=7.3, 1H), 8.81(s, 1H), 7.93 (d, J=2.4, 1H), 7.74 (d, J=9.1, 1H), 7.65 (dd, J=2.4, 9.1,1H), 7.33 (s, 1H), 6.79 (s, 1H), 4.42-4.32 (m, 1H), 4.10 (t, J=6.2, 2H),3.27-3.17 (m, 1H), 2.75 (s, 3H), 2.74 (s, 3H), 2.24 (t, J=7.2, 2H),2.12-2.04 (m, J=9.3, 4H), 2.01-1.93 (m, J=6.8, 2H), 1.68-1.51 (m, 4H).

Example 5-1

7-Fluoro-4-{[trans-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile(Scheme 4)

Tetrakis(triphenylphosphine)palladium (19.8 mg, 0.017 mmol), zinccyanide (15.06 mg, 0.128 mmol),6-bromo-7-fluoro-N-((trans)-4-morpholinocyclohexyl)quinazolin-4-amine(35 mg, 0.086 mmol) and DMA (800 μl) were added to a microwave vial. Thereaction mixture was stirred at 70° C. for 16 h. Additionaltetrakis(triphenylphosphine)palladium (19.8 mg, 0.017 mmol) was added,and the reaction mixture was heated to 150° C. for 10 minutes in amicrowave reactor. The mixture was filtered and purified by masstriggered reverse phase HPLC (ACN/water with 0.1% TFA modifier) toafford the title compound as the TFA salt. MS: 356 (M+1). ¹H NMR (600MHz, DMSO-d₆) δ 9.01 (d, J=7.0, 1H), 8.50 (s, 1H), 8.32 (d, J=7.4, 1H),7.61 (d, J=10.8, 1H), 4.12-4.04 (m, 1H), 3.55-3.50 (m, 4H), 2.46-2.42(m, 4H), 2.25-2.18 (m, 1H), 2.02-1.96 (m, 2H), 1.89-1.83 (m, 2H),1.42-1.26 (m, 4H).The following example in Table 5 was prepared in an analogous manner tothat described in Example 5-1 and general scheme 4.

TABLE 5 Example # Structure Chemical Name MS (M+1) 5-2

5-methyl-4-{[trans-4- (morpholin-4- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 352.0, found 352

Example 6-1

4-({Trans-4-[4-(cyclopropylcarbonyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile(Scheme 6) Step 1:4-{[Trans-4-(piperazin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile,2HCl

A solution of tert-butyl4-{trans-4-[(6-cyanoquinazolin-4-yl)amino]cyclohexyl}piperazine-1-carboxylate(517 mg, 1.18 mmol) in Methanol (10.0 mL) was added to a a 100 mL roundbottom flask. HCl (4M in Dioxane) (10.0 mL, 40.0 mmol) was added, theflask was sealed and its contents were allowed to stir for 4 hours atroom temperature. The reaction mixture was concentrated under reducedpressure to afford the title product as a dihydrochloride salt. MS: 337(M+1).

Step 2:4-({Trans-4-[4-(cyclopropylcarbonyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile

A solution of4-{[trans-4-(piperazin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile,2HCl (11.0 mg, 0.029 mmol), cyclopropanecarboxylic acid (2.54 mg, 0.029mmol), and HATU (16.8 mg, 0.044 mmol) in DMF (0.50 mL) were added to avial. DIEA (0.015 mL, 0.088 mmol) was added, the vial was sealed and itscontents were allowed to react for 30 minutes at room temperature. Themixture was filtered and purified by mass triggered reverse phase HPLC(ACN/water with 0.1% NH₄OH modifier) to afford the title compound. MS:405 (M+1). ¹H NMR (600 MHz, DMSO-d₆): δ 8.90 (d; J=1.74 Hz; 1H); 8.51(s; 1H); 8.24 (d; J=7.53 Hz; 1H); 8.02 (dd; J=8.63; 1.73 Hz; 1H); 7.72(d; J=8.63 Hz; 1H); 4.08-4.12 (m; 1H); 3.61 (s; 2H); 3.40 (s; 2H); 2.51(s; 2H); 2.43 (s; 2H); 2.32-2.35 (m; 1H); 1.99-2.01 (m; 2H); 1.90-1.94(m; 1H); 1.82-1.84 (m; 2H); 1.31-1.43 (m; 4H); 0.63-0.69 (m; 4H).The following examples in Table 6 were prepared in an analogous mannerto that described in Example 6-1 and general scheme 6.

TABLE 6 Example # Structure Chemical Name MS (M+1) 6-2

4-{[trans-4-(4- acetylpiperazin-1- yl)cyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 379.0, found 379 6-3

4-({trans-4-[4-(2,2- dimethylpropanoyl) piperazin-1-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 421.0, found 4216-4

4-({trans-4-[4-(3-fluoro- 2,2- dimethylpropanoyl) piperazin-1-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 439.0, found 4396-5

4-({trans-4-[4-(2-fluoro- 2- methylpropanoyl)piperazin- 1-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 425.0, found 4256-6

4-({trans-4-[4-(2,2- difluoropropanoyl)piperazin- 1-yl]cyclohexyl}amino) quinazoline-6-carbonitrile Calc'd 429.0, found 4296-7

4-({trans-4-[4-(2- fluoropropanoyl)piperazin- 1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 411.0, found 411 6-8

4-[(trans-4-{4-[(1- methylcyclopropyl) carbonyl]piperazin-1-yl}cyclohexyl)amino] quinazoline-6-carbonitrile Calc'd 419.0, found 4196-9

4-[(trans-4-{4-[(3- methyloxetan-3- yl)carbonyl]piperazin-1-yl}cyclohexyl)amino] quinazoline-6-carbonitrile Calc'd 435.0, found 4356-10

4-({trans-4-[4- (methoxyacetyl)piperazin- 1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 409.0, found 409 6-11

4-[(trans-4-{4-[(2S)- tetrahydrofuran-2- ylcarbonyl]piperazin-1-yl}cyclohexyl)amino] quinazoline-6-carbonitrile Calc'd 435.0, found 4356-12

4-({trans-4-[4- (difluoroacetyl)piperazin- 1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 415.0, found 415 6-13

4-[(trans-4-{4-[(3- fluorocyclobutyl)carbonyl] piperazin-1-yl}cyclohexyl)amino] quinazoline-6-carbonitrile Calc'd 437.0, found 4376-14

4-[(trans-4-{4-[(2,2- difluorocyclopropyl) carbonyl]piperazin-1-yl}cyclohexyl)amino] quinazoline-6-carbonitrile Calc'd 441.0, found 4416-15

4-({trans-4-[4- (cyclobutylcarbonyl) piperazin-1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 419.0, found 419 6-16

4-({trans-4-[4- (cyclopentylcarbonyl) piperazin-1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 433.0, found 433 6-17

4-({trans-4-[4- (cyclopropylacetyl) piperazin-1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 419.0, found 419 6-18

4-({trans-4-[4-(oxetan-3- ylacetyl)piperazin-1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 435.0, found 435 6-19

4-({trans-4-[4- (fluoroacetyl)piperazin- 1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 397.0, found 397 6-20

4-[(trans-4-{4- [cyclopropyl(hydroxy) acetyl]piperazin-1-yl}cyclohexyl)amino] quinazoline-6-carbonitrile Calc'd 435.0, found 4356-21

4-[(trans-4-{4-[(3- hydroxycyclobutyl) carbonyl]piperazin-1-yl}cyclohexyl)amino] quinazoline-6-carbonitrile Calc'd 435.0, found 4356-22

4-({trans-4-[4-(3- hydroxypropanoyl) piperazin-1- yl]cyclohexyl}amino)quinazoline-6-carbonitrile Calc'd 409.0, found 409 6-23

4-[(trans-4-{4-[(2R)- tetrahydrofuran-2- ylcarbonyl]piperazin-1-yl}cyclohexyl)amino] quinazoline-6-carbonitrile Calc'd 435.0, found 435

Example 7-1

4-{[Trans-1-methyl-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile(Scheme 7) Step 1: 4-Amino-4-methylcyclohexanone, HCl

To a 20 mL scintillation vial charged with tert-butyl(1-methyl-4-oxocyclohexyl)carbamate (200 mg, 0.880 mmol) was added asolution of hydrochloric acid in dioxane (4M, 3.30 mL, 13.2 mmol). Thereaction mixture was stirred at room temperature for 3 hours. Thevolatiles were evaporated in vacuo to afford the title compound as anHCl salt. MS: 128 (M+1).

Step 2: 4-[(1-Methyl-4-oxocyclohexyl)amino]quinazoline-6-carbonitrile

A 20 mL scintillation vial was charged with4-chloroquinazoline-6-carbonitrile (120 mg, 0.633 mmol),4-amino-4-methylcyclohexanone, HCl (145 mg, 0.886 mmol) and DMA (5 mL).DIEA (0.884 mL, 5.06 mmol) was added, the vial was capped and thecontents stirred at room temperature for 16 hours. The volatiles wereremoved in vacuo, the resulting residue re-dissolved in dichloromethaneand purified by column chromatography on silica gel, ISCO; 12 gprepacked, (0-100% hexanes/ethyl acetate) to afford the title compound.MS: 281 (M+1).

Step 3:4-{[Trans-1-methyl-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile

To a 20 mL scintillation vial charged with4-[(1-Methyl-4-oxocyclohexyl)amino]quinazoline-6-carbonitrile (50.0 mg,0.178 mmol) and DCE (1.25 mL) was added morpholine (0.047 mL, 0.535mmol). The vial was capped and the reaction mixture stirred at roomtemperature for 90 minutes. Sodium triacetoxyborohydride (113 mg, 0.535mmol) was added and the contents stirred for an additional 16 hours. Themixture was diluted with dichloromethane (5 mL), washed with aqueoussodium hydrogen carbonate (saturated, 10 mL), dried (MgSO₄), filteredand the solvent was evaporated under reduced pressure. The resultingresidue was taken up in DMSO (2 mL), filtered and purified by masstriggered reverse phase HPLC (ACN/water with 0.1% NH₄OH modifier) toafford4-((-1-methyl-4-morpholinocyclohexyl)amino)quinazoline-6-carbonitrile asa mixture of cis- and trans-isomers. The mixture was further purified byachiral SFC (ES Pyridyl Amide column, 15%/85% methanol+0.25% DimethylEthyl Amine/CO₂) to afford the title compound (slower eluting). MS: 352(M+1). ¹H NMR (600 MHz, DMSO-d₆): δ 9.78 (br s, 1H); 9.06 (s, 1H); 8.52(s, 1H); 8.03 (d, J=8.6 Hz, 1H); 7.73 (d, J=8.6 Hz, 1H); 7.64 (s, 1H);4.02-3.94 (m, 2H); 3.72-3.63 (m, 2H); 3.55 (br s, 1H); 3.51-3.43 (m,2H); 3.23 (br s, 1H); 3.12-3.07 (m, 2H); 2.55 (br s, 1H); 2.41-2.32 (m,1H); 2.04 (br s, 1H); 1.90 (t, J=12.7 Hz, 2H); 1.65 (br s, 2H); 1.54 (s,3H).The following examples in Table 7 were prepared in an analogous mannerto that described in Example 7-1 and general scheme 7 from commerciallyavailable N-Boc protected cyclohexanones.

TABLE 7 Example # Structure Chemical Name MS (M+1) 7-2

4-{[trans-4-(4- fluoropiperidin-1-yl)-1- methylcyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 368.0, found 368 7-3

4-{[trans-4-(3- hydroxypyrrolidin-1-yl)- 1- methylcyclohexyl]amino}quinazoline-6-carbonitrile Calc'd 352.0, found 352 7-4

4-{[(1S,2S,5S,6R)-5-(4- fluoropiperidin-1- yl)bicyclo[4.1.0]hept-2-yl]amino}quinazoline-6- carbonitrile Calc'd 366.0, found 366

Example 8-1

4-{[(1R,2R,4R or1S,2S,4S)-2-methyl-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile(Scheme 8) Step 1:Trans-4-[(2-methyl-4-oxocyclohexyl)amino]quinazoline-6-carbonitrile

To a 50 mL round bottom flask charged withtrans-4-[7-methyl-1,4-dioxaspiro[4.5]dec-8-yl)amino]quinazoline-6-carbonitrile(0.135 g, 0.416 mmol) and acetone (12 mL) was added p-toluenesulfonicacid monohydrate (0.396 g, 2.08 mmol) and the mixture was stirred atroom temperature for 16 hours. The reaction mixture was concentrated andthe resulting residue diluted with dichloromethane (5 mL), washed withaqueous sodium hydrogen carbonate (saturated, 2×5 mL), dried (MgSO₄),filtered and the solvent was evaporated under reduced pressure to affordthe title compound. MS: 281 (M+1).

Step 2: 4-{[(1R,2R,4R or1S,2S,4S)-2-methyl-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile

Morpholine (0.047 mL, 0.535 mmol) as added to a 20 mL scintillation vialcharged withtrans-4-[(2-methyl-4-oxocyclohexyl)amino]quinazoline-6-carbonitrile(0.050 g, 0.178 mmol) and DCE (4 mL). The vial was capped and thereaction mixture stirred at room temperature for 90 minutes. Sodiumtriacetoxyborohydride (0.113 g, 0.535 mmol) was added and the contentsstirred for an additional 16 hours. The mixture was diluted withdichloromethane (5 mL), washed with aqueous sodium hydrogen carbonate(saturated, 10 mL), dried (MgSO₄), filtered and the solvent wasevaporated under reduced pressure. The resulting residue was taken up inDMSO (2 mL), filtered and submitted for mass-triggered reverse phaseHPLC (ACN/water with 0.1% NH₄OH modifier) to afford the title compound(faster eluting). MS: 352 (M+1). ¹H NMR (600 MHz, CD₃OD): δ 8.70 (s,1H); 8.48 (s, 1H); 7.97 (d, J=8.7 Hz, 1H); 7.76 (d, J=8.7 Hz, 1H);4.08-4.02 (m, 1H); 3.73-3.68 (m, 4H); 3.32-3.27 (m, 1H); 2.64 (br s,4H); 2.41 (br s, 1H); 2.12-2.02 (m, 2H); 1.81-1.72 (m, 1H); 1.48-1.39(m, 2H); 1.21 (q, J=12.1 Hz, 1H); 0.98 (d, J=6.5 Hz, 3H).The following examples in Table 8 were prepared in an analogous mannerto that described in Example 8-1 and general scheme 8.

TABLE 8 Example # Structure Chemical Name MS (M+1) 8-2

4-{[(1S,2S,4S or 1R,2R,4R)-4-(4- fluoropiperidin-1-yl)-2-methylcyclohexyl]amino} quinazoline-6- carbonitrile Calc'd 368.0, found368 8-3

4-{[(1S,2R,4S or 1R,2S,4R)-2-methyl-4- (morpholin-4-yl)cyclohexyl]amino} quinazoline-6-carbonitrile Calc'd 352.0, found 352

Biological Data

Examples of the instant invention were tested by the assay describedbelow and were found to have IRAK4 inhibitory activity. Other assays areknown in the literature and could be readily performed by those of skillin the art.

IRAK4 Kinase Assay

The kinase activity of IRAK4 is determined by its ability to catalyzethe phosphorylation of a fluorescent polypeptide substrate. The extentof phosphorylation is measured using the IMAP technology (MolecularDevices) where the phosphorylated fluorescent substrate binds to thelarge M(III)-based nanoparticles which reduces the rotational speed ofthe substrate and thus increases its fluorescent polarization (FP).

20 μL reaction mixture contains 10 mM TriHCl, pH 7.2, 0.5 nM GST taggedIRAK4 (SignalChem), 100 nM fluorescent peptide substrate (RP7030,Molecular Devices), 100 μM ATP, 1 mM DDT, 1 mM MgCl₂, and 0.01% Tween20. The reaction is initiated by the addition of ATP. After incubationfor 30 minutes at 25° C., 60 μL of Progressive IMAP Reagent (MolecularDevices) is added to stop the reaction. Change in RP7030's FP isdetermined by a FP reader (Analyst HT, LJL BioSystems).

The following table shows the activity data for compounds of the instantinvention.

TABLE 9 Example # IRAK4 IC50 (nM) 1-1 31 1-2 27 2-1 40 2-2 5 2-3 74202-4 303 2-5 7 2-6 9 2-7 6 2-8 16 2-9 113 2-10 82 2-11 15 2-12 58 2-13 62-14 16 2-15 12 2-16 734 2-17 52 2-18 56 3-1 34 3-2 33 3-3 7 3-4 503 3-5908 3-6 768 3-7 96 3-8 2554 3-9 5 3-10 11 3-11 7 3-12 6 3-13 14 3-14 333-15 58 3-16 7 3-17 4 3-18 114 3-19 3 3-20 8 3-21 512 3-22 16 3-23 263-24 11 3-25 53 3-26 46 3-27 8 3-28 47 3-29 11 3-30 17 3-31 10 3-32 153-33 132 3-34 33 3-35 38 3-36 25 3-37 41 3-38 15 3-39 174 3-40 51 3-4170 3-42 5 3-43 9 3-44 15 3-45 6 3-46 7 3-47 872 3-48 256 3-49 131 3-50579 3-51 89 3-52 26 3-53 12 3-54 3 3-55 15 4-1 525 5-1 27 5-2 52 6-1 36-2 11 6-3 8 6-4 9 6-5 12 6-6 16 6-7 14 6-8 15 6-9 14 6-10 16 6-11 116-12 27 6-13 10 6-14 13 6-15 10 6-16 10 6-17 9 6-18 10 6-19 23 6-20 86-21 10 6-22 9 6-23 17 7-1 98 7-2 74 7-3 43 7-4 7 8-1 14 8-2 10 8-3 26

What is claimed is:
 1. A compound according to Formula I:

wherein: X is NH or 0; b is 0 or 1; n is 0, 1, 2, 3 or 4; R₁ and R₂ are independently H and (C₁-C₄)alkyl, or R₁ and R₂ can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic (fused, bridged or spirocyclic) heterocycle containing 3-8 carbon atoms optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said alkyl and heterocycle are optionally substituted with one or more substituents selected from R_(a); R₃ is (C₁-C₄)alkyl wherein two adjacent alkyl groups can join together and form a bridged moiety of 3-6 carbon atoms; R₄ is absent, halo or O_(b)(C₁-C₄)alkyl; R₅ is halo, CN and O(C₁-C₄)alkyl, said alkyl optionally substituted with one or more substituents selected from CN and (C═O)NH₂; R₆ is absent, halo, or O(C₁-C₄)alkyl; R_(a) is independently selected from halo, CF₃, O_(b)(C₁-C₄)alkyl, SO₂(C₁-C₄)alkyl, C(O) O_(b)(C₁-C₆)alkyl, (C═O)_(b)heterocyclyl, wherein said alkyl can come together with another alkyl to form a bridged moiety and wherein said alkyl and heterocyclyl are optionally substituted with R_(b); and R_(b) is independently selected from OH, halo, SO₂(C₁-C₄)alkyl, O_(b)(C₁-C₄)alkyl, and heterocyclyl; or a pharmaceutically acceptable salt or a stereoisomer thereof.
 2. A compound according to claim 1 of Formula I: wherein: X is NH or 0; b is 0 or 1; n is 0, 1, 2, 3 or 4; R₁ and R₂ are independently H and (C₁-C₄)alkyl, or R₁ and R₂ can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic (fused, bridged or spirocyclic) heterocycle containing 3-8 carbon atoms optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said alkyl and heterocycle are optionally substituted with one or more substituents selected from R_(a); R₃ is methyl wherein two adjacent methyl groups can join together and form a bridged moiety of 3-6 carbon atoms; R₄ is absent or (C₁-C₄)alkyl; R₅ is halo, CN and O(C₁-C₄)alkyl, said alkyl optionally substituted with one or more substituents selected from CN and (C═O)NH₂; R₆ is absent, halo, or O(C₁-C₄)alkyl; R_(a) is independently selected from halo, CF₃, O_(b)(C₁-C₄)alkyl, SO₂(C₁-C₄)alkyl, C(O) O_(b)(C₁-C₆)alkyl, heterocyclyl, C═O-tetrahydrofuranyl, wherein said alkyl can come together with another alkyl for form a bridged moiety and wherein said alkyl and heterocyclyl are optionally substituted with R_(b); and R_(b) is independently selected from OH, halo, SO₂(C₁-C₄)alkyl, O_(b)(C₁-C₄)alkyl, morpholinyl and oxetanyl; or a pharmaceutically acceptable salt or a stereoisomer thereof.
 3. A compound according to claim 1 of Formula I: wherein: X is NH or O; b is 0 or 1; n is 0, 1 or 2; R₁ and R₂ are independently H and (C₁-C₄)alkyl, or R₁ and R₂ can be taken together with the nitrogen to which they are attached to form morpholinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolinyl, pyrhexahydrocyclopentaoxazinyl, hexahydropyranopyridinyl, hexahydrofuropyrrolyl, azabicyclooctyl, oxaazabicyclooctyl and azapanyl, said alkyl, morpholinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolinyl, pyrhexahydrocyclopentaoxazinyl, hexahydropyranopyridinyl, hexahydrofuropyrrolyl, azabicyclooctyl, oxaazabicyclooctyl and azapanyl are optionally substituted with one or more substituents selected from R_(a); R₃ is methyl wherein two adjacent methyl groups can come together and form a bridged moiety; R₄ is absent or methyl; R₅ is selected from: Br, F, Cl, CN and O(C₁-C₄)alkyl, said alkyl optionally substituted with one or more substituents selected from CN and (C═O)NH₂; R₆ is absent, halo, or CH₃; R_(a) is independently selected from F, CF₃, O_(b)(C₁-C₄)alkyl, SO₂(C₁-C₄)alkyl, C(O) O_(b)(C₁-C₆)alkyl, heterocyclyl, C═O-tetrahydrofuran, wherein said alkyl can come together with another alkyl for form a bridged moiety and wherein said alkyl and heterocyclyl are optionally substituted with R_(b); and R_(b) is independently selected from OH, halo, SO₂(C₁-C₄)alkyl, O_(b)(C₁-C₄)alkyl, morpholinyl and oxetanyl; or a pharmaceutically acceptable salt or a stereoisomer thereof.
 4. A compound which is selected from: 4-[(trans-4-aminocyclohexyl)amino]quinazoline-6-carbonitrile; trans-N-(6-bromoquinazolin-4-yl)cyclohexane-1,4-diamine; 6-bromo-4-{[trans-4-(morpholin-4-yl)cyclohexyl]oxy}quinazoline; 6-bromo-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine; trans-N′-(6,7-dimethoxyquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine; trans-N′-(6,7-difluoroquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine; 4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazoline-6-carbonitrile; trans-N′-(6-bromoquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine; 4-{[trans-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 6-methoxy-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine; 6-fluoro-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine; N-[trans-4-(morpholin-4-yl)cyclohexyl]-6-(propan-2-yloxy)quinazolin-4-amine; 6-bromo-7-fluoro-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine; 7-fluoro-6-methoxy-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine; 6-chloro-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine; trans-N′-(6-methoxyquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine; [(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)oxy]acetonitrile; 4-[(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)oxy]butanenitrile; 2-[(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)oxy]acetamide; 4-{[(1S,6R)-5-(morpholin-4-yl)bicyclo[4.1.0]hept-2-yl]amino}quinazoline-6-carbonitrile; 4-{[trans-4-(azetidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({cis or trans-4-[(3R or S)-3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({cis or trans-4-[(3R or S)-3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({cis or trans-4-[(3R or S)-3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({cis or trans-4-[(3R or S)-3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-{[cis-4-(azetidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-{[trans-4-(2,3-dimethylmorpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-{[cis-4-(2,3-dimethylmorpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({trans-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[4-(methyl sulfonyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(2R or 2S)-2-(hydroxymethyl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(2R or 2S)-2-(hydroxymethyl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[3-(methyl sulfonyl)pyrrolidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(2S,6S or 2R,6R)-2,6-dimethylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(2S,6S or 2R,6R)-2,6-dimethylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(2S or 2R)-2-methylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(2S or 2R)-2-methylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-{[trans-4-(4-fluoropiperidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({trans-4-[4-(methyl sulfonyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(2-methoxyethyl)amino]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-{[trans-4-(cyclopropylamino)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({trans-4-[(4aS,7aS or 4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-{[trans-4-(hexahydro-2H-pyrano[4,3-b]pyridin-1(5H)-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-{[trans-4-(4-oxa-7-azaspiro[2.5]oct-7-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({trans-4-[2-(fluoromethyl)morpholin-4-yl]cyclohexyl})quinazoline-6-carbonitrile; 4-({trans-4-[(3S)-3-methylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-{[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-{[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({trans-4-[(3R)-3-methylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[cyclopropyl(methyl)amino]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-{[trans-4-(3,3-difluoropiperidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({trans-4-[(3S)-3-hydroxypyrrolidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-{[trans-4-(3-fluoropiperidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-{[trans-4-(3-hydroxy-3-methylpyrrolidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({trans-4-[3-(morpholin-4-yl)azetidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(3R)-3-hydroxypyrrolidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-{[trans-4-(hexahydro-4H-furo[3,2-b]pyrrol-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({trans-4-[(3R)-3-methoxypyrrolidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(3R or 3S)-3-(morpholin-4-ylmethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(3R or 3S)-3-(morpholin-4-ylmethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[4-(morpholin-4-ylmethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-{[trans-4-(pyrrolidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; tert-butyl 4-{trans-4-[(6-cyanoquinazolin-4-yl)amino]cyclohexyl}piperazine-1-carboxylate; 4-({trans-4-[3-(morpholin-4-ylmethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-{[trans-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({trans-4-[(2R or 2S)-2-(trifluoromethyl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(2R or 2S)-2-(trifluoromethyl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[(1R,5S)-8-oxa-3-azabicyclo[3.2.1]oct-3-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({[trans-4-(2,2-dimethylmorpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({trans-4-[(3R)-3-(propan-2-yl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({[trans-4-(4,4-difluoroazepan-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({[trans-4-(4,4-difluoropiperidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({[trans-4-(3-hydroxypyrrolidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-[(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)oxy]butanamide; 7-fluoro-4-{[trans-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 5-methyl-4-{[trans-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({trans-4-[4-(cyclopropylcarbonyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({[trans-4-(4-acetylpiperazin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-({trans-4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[4-(3-fluoro-2,2-dimethylpropanoyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[4-(2-fluoro-2-methylpropanoyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[4-(2,2-difluoropropanoyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[4-(2-fluoropropanoyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-[(trans-4-{4-[(1-methylcyclopropyl)carbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile; 4-[(trans-4-{4-[(3-methyloxetan-3-yl)carbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile; 4-({trans-4-[4-(methoxyacetyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-[(trans-4-{4-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile; 4-({trans-4-[4-(difluoroacetyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-[(trans-4-{4-[(3-fluorocyclobutyl)carbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile; 4-[(trans-4-{4-[(2,2-difluorocyclopropyl)carbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile; 4-({trans-4-[4-(cyclobutylcarbonyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[4-(cyclopentylcarbonyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[4-(cyclopropylacetyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[4-(oxetan-3-ylacetyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-({trans-4-[4-(fluoroacetyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-[(trans-4-{4-[cyclopropyl(hydroxy)acetyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile; 4-[(trans-4-{4-[(3-hydroxycyclobutyl)carbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile; 4-({trans-4-[4-(3-hydroxypropanoyl)piperazin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile; 4-[(trans-4-{4-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperazin-1-yl}cyclohexyl)amino]quinazoline-6-carbonitrile; 4-{[trans-1-methyl-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-{[trans-4-(4-fluoropiperidin-1-yl)-1-methylcyclohexyl]amino}quinazoline-6-carbonitrile; 4-{[trans-4-(3-hydroxypyrrolidin-1-yl)-1-methylcyclohexyl]amino}quinazoline-6-carbonitrile; 4-{[(1S,2S,5S,6R)-5-(4-fluoropiperidin-1-yl)bicyclo[4.1.0]hept-2-yl]amino}quinazoline-6-carbonitrile; 4-{[(1R,2R,4R or 1S,2S,4S)-2-methyl-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile; 4-{[(1S,2S,4S or 1R,2R,4R)-4-(4-fluoropiperidin-1-yl)-2-methylcyclohexyl]amino}quinazoline-6-carbonitrile; 4-{[(1S,2R,4S or 1R,2S,4R)-2-methyl-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile); or a pharmaceutically acceptable salt or stereoisomer thereof.
 5. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim
 1. 